Percutaneous treatment of the left main coronary artery in older adults. Impact of frailty on mid-term results

INTRODUCTION

The left main coronary artery (LM) supplies 84% of the blood flow to the left ventricle in patients with right dominance,1 making LM disease the coronary lesion with the worst prognosis. The prevalence of this disease is not negligible, as it is found in 4.8% of coronary angiograms,2 highlighting the prognostic importance of these lesions. Conservative treatment is a rarely a feasible option due to the high rate of cardiac adverse events during short-term follow-up, with a mortality rate exceeding 50%.3

Coronary artery bypass grafting (CABG) has traditionally been the most widely accepted revascularization strategy.4 In recent years, there have been significant pharmacological and technological improvements in percutaneous revascularization techniques, such as drug-eluting stents and intracoronary diagnostic techniques.5 These improvements, together with comparative studies, have prompted discussion on the various alternatives.6 Presently, the choice of revascularization strategy should be based on the complexity of the coronary anatomy and surgical risk.7

However, evidence is limited in older adults who are scarcely represented in classic studies. Furthermore, in these patients, frailty is a frequent and unstudied characteristic that can influence their prognosis. In this special population, CABG is usually ruled out due to high-surgical risk. On the other hand, percutaneous coronary intervention (PCI) could be a potential therapeutic option, although with little evidence to date.8 Consequently, we postulated that PCI of the LM might be feasible and safe in older patients, with a low incidence of associated complications and an acceptable rate of major adverse cardiac events (MACE) during follow-up.

METHODS

Study design

We conducted a retrospective, single-center study of older patients diagnosed with LM disease who underwent PCI. The study aimed to evaluate mid-term clinical outcomes and examine the prognostic significance of frailty in these patients. The study protocol was approved by the local clinical research ethics committee according to institutional and good clinical practice guidelines. Recruitment took place from January 2017 to December 2021 at Hospital Universitario Reina Sofía (Cordoba, Spain). Patients were eligible if they were aged ≥ 75 years at the time of LM disease diagnosis, and PCI was chosen as the treatment after deliberation by heart team discussion, or due to instability requiring emergent revascularization. Exclusion criteria consisted of end-stage chronic diseases, patients under palliative care, contraindications to dual antiplatelet therapy, and incomplete follow-up data. Included patients were grouped according to frailty status, determined by the FRAIL scale, with patients scoring 3 or more points considered frail.9 Definitions are shown in the supplementary data.

Outcomes

The main objective of the study was to describe mid-term clinical outcomes in older patients undergoing LM-PCI. We also aimed to compare clinical events according to the presence of frailty. The primary endpoint was a composite of MACE, defined as a composite of cardiovascular death (including death of uncertain cause), nonfatal myocardial infarction, the need for new revascularization, and stroke. Secondary outcomes were the individual components of MACE and all-cause mortality.

Angiographic analysis

Quantitative analysis of the coronary arteries was performed using the validated CAAS system (Pie Medica Imaging, the Netherlands). The basal anatomy of the LM bifurcation with the anterior descending artery and the circumflex artery was classified according to the Medina classification.10 The measurements analyzed included the reference diameter of the LM and its percentage of stenosis. The complexity of the coronary anatomy was studied using the SYNTAX scale.6

Statistical analysis

Categorical data are presented as counts (percentages), while continuous data are expressed as mean ± standard deviation or median [interquartile range]. Between-group comparisons were performed using the chi-square test or the Fisher exact test for categorical variables and the Student t-test or the Mann-Whitney U test for continuous variables. Kaplan-Meier curves and Cox regression models were used to analyze clinical events according to frailty. Inverse probability of treatment weighting (IPTW) was used to account for clinical differences between the 2 groups.11 Propensity scores were calculated using a logistic regression model that included the following covariates: age, sex, left ventricular ejection fraction, atrial fibrillation, chronic kidney disease, anemia, and chronic obstructive pulmonary disease. Standardized mean differences before and after weighting were used to evaluate the balance of the groups regarding the covariates. A difference of < 10% was considered to indicate a satisfactory balance. The distributions of the propensity scores before and after weighting were plotted to assess the degree of overlap between the 2 groups. Confidence intervals for the IPTW coefficients were obtained using robust sandwich-type variance estimators (figure 1 of the supplementary data).12 All tests were 2-tailed and significance was set at P < .05. Statistical analyses were performed using SPSS software (V 24; IBM Corp., United States) and R software (V4.0.3; R Foundation for Statistical Computing, Austria).

Figure 1. Main events to follow-up. CV, cardiovascular; MACE, mayor adverse cardiovascular events; MI, myocardial infarction; NS, nonsignificant; PCI, percutaneous coronary intervention. * P < .005.

RESULTS

During the study period, our hospital treated 437 patients with significant LM lesions percutaneously. Of them, a total of 140 patients met the inclusion criteria and were included in the analysis (figure 2 of the supplementary data).

Figure 2. Kaplan-Meier Curves of the primary outcome and mortality. CV, cardiovascular; MACE, major adverse cardiovascular events.

Baseline characteristics

The baseline clinical characteristics, clinical presentation and antithrombotic treatment administered are detailed in table 1. The median age of the patients was 80 [78-84] years and 36% (51 patients) were women. Most of the patients had a history of hypertension (84%, 118 patients) and 58% (81 patients) were diabetic. More than a third of the patient cohort had a previous personal history of ischemic heart disease (37%, 52 patients) and 33% (46 patients) had chronic kidney disease. Among noncardiovascular comorbidities, active cancer was present in 11 patients (8%) and prior blood transfusions had been required in 16 patients (11%). The mean EuroSCORE II was 3.07 [1.96-5.7] to assess surgical risk. Forty-eight patients (34%) had left ventricular systolic dysfunction at the time of revascularization.

Table 1. Patients’ baseline characteristics

The most common clinical presentation was acute coronary syndrome (85 patients, 61% of cases). Among these, onset consisted of ST-segment elevation myocardial infarction (STEMI) in 9 patients (6%), non-ST-segment elevation myocardial infarction in 61 patients (44%), and unstable angina in 15 patients (10%). The remaining patients (55, 39%) presented with chronic coronary syndrome.

A total of 104 patients (74%) were discharged with dual antiplatelet therapy. The main combination was aspirin and clopidogrel (61 patients, 43%). In 36 patients (26%), initial triple therapy (anticoagulation and dual antiplatelet therapy) was chosen due to concurrent conditions requiring chronic oral anticoagulation.

Based on the FRAIL scale, almost half of the patients (68 patients, 49%) met clinical criteria for frailty at the time of revascularization. The baseline characteristics of frail and nonfrail patients are shown in table 1. No statistically significant differences were found in terms of age, main cardiovascular risk factors or noncardiovascular comorbidities between the 2 groups. However, compared with nonfrail patients, those with frailty were more likely to be female (49% vs 25%; P = .004), to have atrial fibrillation (22% vs 10%; P = .041), a higher EuroSCORE level (3.80 vs 2.76; P = .010), and anemia (28% vs 14%; P = .040), and consequently a lower hematocrit and hemoglobin value (36.6% vs 39.6%; P = .031 and 12.16 mg/dL vs 13.02 mg/dL; P = .017, respectively).

Angiographic and procedural characteristics

Angiographic and procedural data are shown in table 2. The arterial access of choice was radial access (81% of procedures, 113 patients). A median SYNTAX score of 21 [15-29.5] was observed in 96 patients (68%) with multivessel disease, and 62 patients (44%) had a SYNTAX score > 22. The most common angiographic involvement of the LM was the distal segment (61%, 86 patients), while the most common plaque distribution according to the Medina classification was “1,1,1” (35 patients, 41% of LM bifurcation lesions). The strategy of choice for the treatment of the bifurcation was the provisional stent strategy (85% of LM bifurcation lesions, 73 patients), while the upfront 2-stent strategy was used in only 13 patients (15% of the LM bifurcation lesions). The mean diameter of the LM was 4.1 [± 3.5-4.5] mm with a mean angiographic stenosis of 62% (± 7). In 59 patients (42%), the procedure was guided using intravascular imaging techniques (58 patients using intracoronary ultrasound and 1 patient using coherence tomography). Coronary physiology was used in 5 patients (4%) to guide the need for revascularization or to check the result after percutaneous treatment. In 7 (5%) patients, mechanical support was required, either due to cardiogenic shock, or as a preventive measure in high-risk angioplasty (5 patients with an intra-aortic balloon pump and 2 with an Impella CP device [Abiomed, United States]). Intraprocedural complications occurred in 8 patients (6%), including a major complication in 4 patients (3 intraprocedural deaths and 1 cardiogenic shock), and a minor complication in 4 patients (1 coronary dissection with Thrombolysis in Myocardial Infarction (TIMI) grade 3 distal flow, 1 pseudoaneurysm, and 2 bleeding events from the femoral access resolved by stent implantation). The LM diameter was larger in patients with frailty than in those without (4 mm [4-4.5] vs 3.5 mm [3.5-4.5]; P = .023), a paradoxical finding since the percentage of women was higher in the group with frailty percentage of women. However, this information did not seem to be clinically relevant. No other clinically relevant differences were found between the 2 groups (table 2).

Table 2. Patients’ angiographic and procedural characteristics

Clinical results at follow-up

After a median follow-up of 19 months [5-35], a total of 40 (29%) MACE were recorded: 3 (2%) patients had a nonfatal myocardial infarction, 7 (5%) patients required repeat revascularization (3 for restenosis of the LM, and 4 in a different vessel), and 30 patients (21%) died of cardiac and/or uncertain causes. No strokes were reported during follow-up. Sixteen patients (11%) died of noncardiac causes during follow-up.

Clinical outcomes are presented in figure 1 and figure 2. No independent predictor of MACE was identified. The independent predictors of all-cause mortality were left ventricular ejection fraction (hazard ratio [HR], 0.90 [0.96-0.99]; P = .014), chronic kidney disease (HR, 2.26 [1.16-4.42]; P = .017), and particularly the presence of frailty (HR, 2.42 [1.17-5.02]; P = .018) (table 1 of the supplementary data). The primary endpoint of MACE occurred in 24 (35%) patients in the frail group and in 16 (22%) patients in the nonfrail group (HR, 1.61 [0.79-3.28]; P = .193). Frail patients had an increased risk of cardiovascular mortality: 21 (31%) vs 9 (13%); HR, 2.64 (1.21-5.77); P = .015. All-cause mortality was also more frequent in the frail group: 33 (49%) vs 13 (18%); HR, 2.94 (1.55-5.59); P = .001). The events during follow-up are presented in table 2 of the supplementary data. After IPTW adjustment, only the difference in all-cause mortality remained significant (HR, 1.95 [1.02-3.75]; P = .046). Survival analysis of the weighted population is shown in figure 3.

Figure 3. Kaplan-Meier Curves of the secondary outcomes. CV, cardiovascular; IPTW, inverse probability of treatment weighting; MACE, major adverse cardiovascular events.

DISCUSSION

The present study describes the feasibility of LM-PCI in a cohort of older patients. The main results were as follows: a) the rate of MACE at mid-term follow-up was 29%, mainly driven by cardiovascular and/or uncertain cause death; b) a high percentage of frailty was found in our population (49%); c) frail patients had a 2-fold increased risk of all-cause mortality during follow-up (HR, 1.95 [1.02-3.75]; P = .046) (figure 4).

Figure 4. Central illustration. Results of percutaneous treatment of LM in elderly patients and impact of frailty. CV, cardiovascular; LM, left main coronary artery; MACE, major adverse cardiovascular events; MI, myocardial infarction; NS, non-significant; PCI, percutaneous coronary intervention.

The treatment of LM disease has traditionally been surgical, given the complexity involved and significant prognostic impact.13 However, the marked advances in interventional cardiology in recent decades have modified the approach.14,15 Contrasting evidence from clinical trials and meta-analyses shows that percutaneous treatment has similar results to surgical approaches in terms of mortality, acute myocardial infarction, and stroke at 5 years of follow-up.16 This shift has is reflected in the evolving recommendations in clinical practice guidelines, and the current European revascularization guidelines assign a grade of recommendation IA to both surgical and percutaneous strategies for the treatment of LM disease when the anatomy is not complex (SYNTAX < 22), and a class IIa recommendation for cases of intermediate complexity (SYNTAX 23-32).7

Nevertheless, the population analyzed in the study has specific clinical characteristics, and is not usually represented in large clinical trials (older patients and those with frailty and a high burden of associated comorbidities). These variables are not systematically included in surgical risk scores but are generally taken into account in routine clinical practice and often influence heart team decisions on the treatment strategy.17 Therefore, because this particular patient cohort is often excluded from research, there are no conclusive data on the benefit of percutaneous revascularization.

Our results are in line with those of previous registries in terms of MACE and all-cause mortality, as well as the association between age and a marked incidence of mortality due to noncardiac causes during follow-up. However, unlike earlier studies, we observed no differences in cardiovascular mortality, despite these patients having a more complex coronary anatomy than younger patients.18 In this regard, our study cohort had a median SYNTAX score of 21, and 44% of the patients had a score above 22. Like previous studies, this SYNTAX index score was not associated with a higher probability of cardiac events during follow-up in this special population.

In the present study, rates of acute myocardial infarction and new revascularization of the target lesion were lower than in other cohorts. Although it is difficult to make direct comparisons, we postulate that the use of new-generation drug-eluting stents and a higher proportion of revascularization guided by intracoronary diagnostic techniques may have influenced this finding. However, the use of intracoronary imaging techniques in our study was relatively low (42%) considering their benefit in patients with complex coronary lesions.19

In recent years, there has been growing interest in understanding the impact of comorbidities and frailty in older patients with cardiovascular disease.20,21 Several studies have compared invasive strategies with conservative approaches in older patients, demonstrating benefits for revascularization.22,23 However, the MOSCA-FRAIL trial compared both strategies in frail patients and observed that an invasive strategy did not confer additional benefit compared with conservative management of these patients, despite a fairly low percentage of LM disease.24 In our study, we observed a 2-fold increase in the risk of all-cause mortality in patients with frailty, suggesting the need to add systematic evaluation of frailty in older patients undergoing LM-PCI. Such assessment can aid in selecting the optimal therapeutic strategy, taking into account the likelihood of mortality during follow-up, irrespective of the application of an invasive strategy in coronary disease. These results, moreover, are consistent with other cardiovascular diseases with significant prevalence and mortality, such as heart failure.25

Study limitations

The present study has several limitations. First, it has the limitations inherent to its observational and retrospective design. Although the sample size is relatively small, it represents the largest study specifically focused on LM-PCI in older patients and analyses associated comorbidities and their impact on cardiovascular adverse events. Second, the absence of a control group receiving conservative treatment hinders the ability to draw more robust conclusions on the safety and efficacy of LM-PCI in these patients. In addition, the selection of cutoff points (age ≥ 75 years) to define this cohort of older patients was arbitrarily based on the exclusion criteria of the main clinical trials previously published. A high percentage of patients with frailty may not have undergone revascularization and would therefore have been excluded from the study. Regarding the prognostic significance of frailty, although we used IPTW to reduce confounding bias, we cannot rule out the possibility of residual confounding due to unmeasured covariables. Furthermore, there are no data on bleeding events during follow-up, which is an important concern given the impact of antiplatelet therapy in these patients. Finally, the percentage of intracoronary imaging use was lower than expected.

CONCLUSIONS

In real-life patients with advanced age and multiple associated comorbidities, percutaneous treatment of LM could be considered a feasible option, with an acceptable incidence of adverse cardiovascular events during follow-up and a low incidence of complications associated with the procedure. Frailty was an independent predictor of all-cause mortality during follow-up. When weighing the risks of LM-PCI in older patients, frailty should be taken into account in the therapeutic decision-making process.

FUNDING

None.

ETHICAL CONSIDERATIONS

The study protocol was approved by the Local Clinical Research Ethics Committee according to institutional and Good Clinical Practice guidelines. All patients signed the informed consent for publication. The authors confirm that sex and gender variables have been considered in accordance with the SAGER guidelines.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the preparation of the study.

AUTHORS’ CONTRIBUTIONS

I. Gallo, M. Alvarado and J. Perea contributed to data collection. R. González-Manzanares performed the statistical analysis. J. Suárez de Lezo and M. Romero contributed to the interpretation of the results. I. Gallo and F. Hidalgo wrote the manuscript. S. Ojeda and M. Pan reviewed the manuscript.

CONFLICTS OF INTEREST

S. Ojeda is associate editor of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial processing of the manuscript has been followed. S. Ojeda has received consulting fees from Medtronic and Edwards and speaker fees from Philips, World Medical and Boston Scientific and is holder of a research grant (PI21/00949) from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III). M. Pan has received speaker fees from Abbott, Boston Scientific, World Medical and Philips and holds a research grant (PI21/00949) from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III). The remaining authors declare no conflicts of interest.

SUPPLEMENTARY DATA

REFERENCES